The long range objective of this laboratory is to develop new treatments for cancer, using agents that regulate receptor function. A distinctive feature of our approach has been our original hypothesis, proposed in 1983 and supported by our published results, that monoclonal antibodies (MAbs) which block binding of ligand to the EGF receptor might be effective anticancer agents. Our recent findings demonstrate that MAb-mediated epidermal growth factor (EGF) receptor blockade can greatly augment the antitumor activity of chemotherapeutic agents. Synergistic cytotoxicity and tumor eradication were observed against well established xenografts of both a squamous carcinoma and a breast adenocarcinoma when MAb treatment was combined with maximally tolerated doses of doxorubicin, Taxol, or cisplatinum. Treatment with either agent alone had only modest activity. In this SPORE grant, we will explore mechanism(s) which explain the capacity of chemotherapy plus blockade of signal transduction mediated by the EGF receptor to produce such striking antitumor activity against breast cancer. The Specific Aims for this project are as follows. Specific Aim 1: to explore the mechanisms of synergistic antitumor effects of cisplatinum. Taxol. and doxorubicin when combined with anti-EGF receptor MAb therapy against breast adenocarcinoma cell likes. This focuses on biochemical regulatory events in which we have evidence that the effects of EGF receptor blockade and chemotherapy may converge. Specific Aim 2: to characterize changes in cell cycle regulation by cyclins. cyclin dependent kinases, and their inhibitors in breast cancer cells following EGF receptor blockade. alone and in combination with chemotherapy. Specific Aim 3: to determine whether receptor blockade by anti-EGF -receptor MAb can reverse chemotherapy resistance in breast cancer cell lines. Specific Aim 4: to assess the effects of anti-erbB-2 MAb 4D5 alone and in combination with MAb 225, upon cyclin dependent kinase activity in breast cancer cells. The results of these investigations will be applied directly to the design of clinical trials combining our human chimeric anti-EGF receptor MAb and chemotherapy for the treatment of breast cancer.